#623

Melatonin is complex as it has effects on a number of levels.

I think the timing of melatonin release/dosing is very important.

However, the body creates melatonin to protect particularly mitochondrial DNA.

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#624

Oops, I forgot to include the circadian rhythm PD paper in my previous post.

Circadian rhythms, Neuroinflammation and Oxidative Stress in the Story of Parkinson’s Disease

#625

Same question, answer by Chat GPT-4.5 Deep research: ChatGPT - Aberrant Splicing in PD

#626

NIH preprint just published: Novel reporter of the PINK1-Parkin mitophagy pathway identifies its damage sensor in the import gate 2025

Damaged mitochondria can be cleared from the cell by mitophagy, using a pathway formed by the recessive Parkinson’s disease genes PINK1 and Parkin. How mitochondrial damage is sensed by the PINK1-Parkin pathway, however, remains uncertain. Here, using a Parkin substrate-based reporter in genome-wide screens, we identified that diverse forms of mitochondrial damage converge on loss of mitochondrial membrane potential (MMP) to activate PINK1. Consistently, the MMP but not the presequence translocase-associated motor (PAM) import motor provided the essential driving force for endogenous PINK1 import through the inner membrane translocase TIM23. In the absence of TIM23, PINK1 arrested in the translocase of the outer membrane (TOM) during import. The energy-state outside of the mitochondria further modulated the pathway by controlling the rate of new PINK1 synthesis. Our results identify separation of PINK1 from TOM by the MMP, as the key damage-sensing switch in the PINK1-Parkin mitophagy pathway.
Highlights

  • MFN2-Halo is a quantitative single-cell reporter of PINK1-Parkin activation.
  • Diverse forms of mitochondrial damage, identified in whole-genome screens, activate the PINK1-Parkin pathway by disrupting the mitochondrial membrane potential (MMP).
  • The primary driving force for endogenous PINK1 import through the TIM23 translocase is the MMP with the PAM import motor playing a supporting role.
  • Loss of TIM23 is sufficient to stabilize PINK1 in the TOM complex and activate Parkin.

Importantly, the proposed model also points to how the PINK1-Parkin pathway may be pharmacologically tuned to promote clearance of damaged mitochondria in disorders caused by mitochondrial damage. Small molecules that upregulate glycolysis, such as the PGK1 activator terazosin, may help support PINK1-Parkin surveillance of mitochondrial damage, by providing ATP needed for new PINK1 synthesis and PINK1-Parkin activation. This may be particularly critical in sporadic Parkinson’s disease, where energy deficiency is likely present in the affected dopamine neurons. Additionally, the MMP threshold of PINK1-Parkin activation may be lowered by decreasing mitochondrial ATP levels. This may have an effect that is similar to MTK458, a PINK1 activator under development by Mitokinin/AbbVie, which was shown to lower the CCCP dose required for PINK1-Parkin activation, similar to the effect of oligomycin observed here. Conversely, small molecules that stabilize the binding site for PINK1 in the TOM complex, buttressed by TOMM5 and TOMM7, may allow PINK1 stabilization at a higher MMP. Either strategy – strengthening PINK1 binding to the TOM translocase or lowering the driving force through the TIM23 translocase – would have a similar effect: increasing the sensitivity of the PINK1-Parkin mitophagy pathway for damaged mitochondria. Finally, we anticipate the MFN2-Halo reporter will help aid drug discovery, as a quantitative, single-cell reporter that is orthogonal to the widely used mitophagy-based reporters.

#627

Parkinson's disease - #618 by adssx by @adssx states “cutting the n. vagus … protects against PD”

my take:

  1. one of the early symptoms is constipation
  2. anticholinergic drugs often cause constipation this seems contradictory
    The MAYOR question however may be : can anticholinergic drugs not only treat some symptoms but also prevent progression of early disease.
#628

They’ve been used for a long time in PD and don’t seem to have any neuroprotective effect.

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#629

Press: Men’s immune response to brain protein may explain their higher rates of Parkinson’s disease 2025

In recent years, LJI scientists have found increasing evidence that autoimmunity plays a role in the onset of Parkinson’s disease. Their recent study in the Journal of Clinical Investigation shows that PINK1 appears to mark some brain cells for immune cell attack.
PINK1 means no harm. The protein actually helps brain cells regulate their mitochondria—the cellular structures that provide energy for a cell. The researchers found that some people with Parkinson’s disease have T cells that mistakenly see PINK1 as a red flag. These T cells may target brain cells that express PINK1, contributing to inflammation and brain cell death.
The new research may help explain why Parkinson’s disease is around twice as common in men as in women. The LJI team found that men with Parkinson’s disease had a six-fold increase in PINK1-specific T cells, compared with healthy male study participants. Women with Parkinson’s disease showed only a 0.7-fold increase in PINK1-specific T cells, compared with healthy female study participants.

Paper: PINK1 is a target of T cell responses in Parkinson’s disease 2024

Within the brain, activation of resident microglia and astrocytes leads to the expression of proinflammatory cytokines, directly inducing neurotoxicity and recruiting immune cells, such as T cells, from the periphery.
T cell reactivity in PD is not associated with early time points or other clinical characteristics.
Not all patients with PD have α-syn–specific T cell reactivity (15, 16). To determine whether patients with PINK1-specific T cells also have α-syn–specific T cell reactivity, we correlated the total magnitude of reactivity against PINK1 with the total magnitude against α-syn (n = 53 participants that responded to either PINK1 or α-syn, Supplemental Figure 3). There was no correlation between reactivity for the 2 proteins and no significant overlap in response to both antigens (2-tailed Fisher’s exact test, P = 0.168).
Our previous work (15, 16) and the work of others (17, 45) have shown that α-syn is a target of peripheral T cell responses in some PD patients. However, not all PD patients possess these autoinflammatory T cells, and for those who do, their frequency wanes over the course of the disease (15). We have also previously shown that τ is recognized by T cells broadly in the population irrespective of age and disease status (39).
In conclusion, our study has identified PINK1 as a common autoantigenic target of T cells in PD. These responses are predominantly associated with male PD individuals, multiple secreted cytokines toward PINK1 were observed, and specific epitopes and corresponding restricting HLA alleles are reported. These results reinforce the need for studying PD in the context of the immune system, with the goal of developing personalized immune-based therapies.

Can’t wait for the azathioprine trial results!

#630

A sub-study of azathioprine in Parkinson’s 2022

This will provide information on whether azathioprine is able to ‘correct’ the Parkinson’s immune profile and reduce inflammatory immune cells entering the brain, which will indicate whether it should be further tested as a future Parkinson’s treatment.
Dr.Williams-Gray – “This trial will allow us to test a brand new strategy of suppressing the immune response to slow the progression of Parkinson’s disease. Our primary measure of the efficacy of azathioprine will be how it affects movement and balance. But in addition to testing whether the drug has a clinical benefit, we want to understand precisely how it is altering the immune system in Parkinson’s. This additional funding from Cure Parkinson’s will allow us to investigate this in both the blood and cerebrospinal fluid – the fluid that bathes the brain. We already know that immune cells cross from the blood into the brain in Parkinson’s and we think this might be important in driving faster disease progression. The key question that this sub-study will address is whether azathioprine treatment can reduce the entry of these cells into the brain – so helping us to understand how the drug might have an effect on this disease.”

@John_Hemming @DrFraser: if correct, this might explain the potential benefits of sirolimus (via immunosuppression rather than mTOR inhibition) in PD despite no brain penetrance. (At least early in the disease?)

[EDIT: results of that trial expected in the next few weeks]

#631

If Parkinsons is primarily an autoimmune disease. The fact that there may be autoimmunity in the process does not, however, mean it is upstream. Hence there could be some symptomatic benefit from that. It is good to relieve symptoms, but the cause needs to be clarified to make the most progress.

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#632

ChatGPT 4.5 says:

If the hypothesis regarding rapamycin’s peripheral immunomodulation (particularly suppression of harmful T-cell responses, such as those targeting PINK1) is correct, it would have profound implications for its potential use in Parkinson’s disease (PD):

1. Symptomatic Relief vs. Disease Modification

  • Symptomatic relief means managing symptoms without altering the underlying disease mechanisms.
  • Disease modification refers to interventions that actually slow or halt disease progression by addressing fundamental pathogenic mechanisms.

In this scenario, rapamycin would primarily function as a disease-modifying therapy rather than merely providing symptomatic relief. Here’s why:

  • If immune activation (e.g., T-cell responses against PINK1) contributes directly to neuronal injury or neurodegeneration, suppressing this mechanism would likely reduce ongoing neuronal damage, not just mask symptoms.
  • Rapamycin’s immunosuppressive effects, therefore, might slow or even halt the progression of neuronal loss by preventing further immune-mediated harm.

2. Preventive Use (Before Diagnosis)

Rapamycin would likely be highly beneficial as a preventive strategy, especially for high-risk populations (e.g., those with family history, genetic predispositions, or identified elevated immune responses such as high PINK1-specific T cells):

  • Prophylactic intervention could significantly reduce or delay the onset of PD by suppressing harmful T-cell-mediated inflammation before substantial neuronal damage occurs.
  • Earlier intervention could prevent the cascade of inflammation and neurodegeneration altogether or substantially delay its initiation.

3. Use After Diagnosis

Rapamycin could also potentially provide significant benefits after diagnosis, although the magnitude and nature of these benefits would depend on timing:

  • Early-stage patients might experience substantial disease-modifying effects if initiated soon after diagnosis, preserving neurons and function.
  • In advanced stages, effectiveness may be more limited, given that significant neuronal loss has already occurred. Still, immunomodulation could prevent further progression or protect remaining neuronal populations.

4. Practical Implications and Considerations

  • Combination therapy: Rapamycin might be most effective when combined with other disease-modifying or symptomatic treatments (dopaminergic therapies, neuroprotectants, or lifestyle interventions).
  • Dosing and timing: Optimal therapeutic windows, dosing schedules (intermittent versus daily), and personalized medicine approaches (tailored immunological biomarkers) would become critical.

Conclusion

If the current immune-driven hypothesis is correct, rapamycin could have a robust disease-modifying (rather than purely symptomatic) role. Its potential effectiveness could span from preventing onset in high-risk individuals to slowing disease progression after diagnosis, especially if initiated early.

Future research should clarify optimal timing, dose regimens, and patient populations that will benefit most significantly from such immunomodulatory strategies.

I think it’s smart. Hopefully we’ll soon know more with the azathioprine trial results. I hope they’ll stratify the results by gender.

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#633

If the current immune-driven hypothesis is correct,

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#634

You’re right. I asked further questions, answer:

If autoimmunity or inflammatory T-cell responses (like those targeting PINK1) in Parkinson’s disease (PD) are genuine but secondary events—meaning they are triggered by earlier pathological processes rather than being primary or causal—it would significantly shift therapeutic expectations and strategies:

1. Implications for Disease Modification

  • If autoimmune responses occur downstream of an initial insult (e.g., mitochondrial dysfunction, accumulation of α-synuclein, environmental triggers, gut-brain axis disruptions), then immunosuppression (like rapamycin treatment) might still slow disease progression but may not stop it completely.
  • Partial disease modification: Rapamycin could interrupt the self-perpetuating inflammatory loop, slowing neurodegeneration by reducing collateral immune damage.
  • However, fundamental disease drivers (such as mitochondrial dysfunction or protein misfolding) would continue independently, meaning progression could still occur at a slower rate.

2. Symptom Relief vs. Slowing Disease

  • Rapamycin or similar immunomodulators might significantly slow disease progression if immune-driven inflammation exacerbates neuronal loss.
  • Even if autoimmune responses are secondary, they could still accelerate and amplify neuronal injury. Interrupting this mechanism might delay disability and preserve quality of life.
  • However, these treatments might not prevent eventual progression, as the underlying triggers persist. Thus, they’d be “disease-modifying,” but only partially so.

3. Therapeutic Timing and Effectiveness

  • Immunotherapy might be most effective earlier in disease, after initial pathology but before extensive autoimmune amplification occurs.
  • Starting treatment after extensive neuronal loss or widespread inflammation has already occurred might be too late for substantial benefit, as the damage may be irreversible or self-sustaining independently of the autoimmune component.

4. Combination Treatments and Multimodal Approaches

  • If autoimmunity is secondary, the most promising therapeutic strategy would likely be a multimodal approach, combining:
    • Immunomodulators (like rapamycin) to limit secondary immune damage.
    • Primary-pathology targeted therapies (e.g., mitochondrial enhancers, α-synuclein aggregation inhibitors, antioxidants, or neuroprotective agents) to target upstream drivers.
    • Symptomatic treatments (dopaminergic drugs, deep-brain stimulation) for immediate quality-of-life improvements.

5. Biomarker Development and Personalized Medicine

  • If autoimmune markers (such as PINK1-specific T-cells) reflect secondary responses, they would be excellent markers of ongoing inflammatory processes rather than early predictive biomarkers.
  • This would facilitate personalized medicine approaches, where immune interventions are tailored according to the intensity of the inflammatory response, even if secondary.

Conclusion

If autoimmunity in PD is secondary, rapamycin and related immune-targeted therapies would still have significant therapeutic value by mitigating immune-related collateral damage. However, to comprehensively treat or prevent PD, we’d need to identify and address the initial upstream events simultaneously or separately.

Thus, a nuanced therapeutic approach would include both upstream interventions (to target root causes) and immunomodulation (to limit secondary inflammatory damage), thereby providing the best chance to meaningfully slow or halt disease progression.

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#635

This is why I get stressed about identifying causes. If the cause can be mitigated then we end up with fewer symptoms to worry about.

Hence if the cause is a shortage of melatonin increasing melatonin levels (at the right time and ideally in the right place, but otherwise systemically) should reduce the effects. The problem, however, is that if the problem results in damage to mtDNA simply increasing melatonin levels won’t necessarily fix the mtDNA even if it stops it being damaged as quickly.

Research that would be useful is more of a study of CSF levels. It would be possible to see if blocking the pineal recess in an animal model causes Parkinsons for example.

I would be inclined to see what further study could be done in some way of CSF melatonin levels. The problem is that this varies from place to place in the CSF and the best places to measure are also the hardest places to measure.

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#636

If that hypothesis has some truth in it, then interventions that can’t cross the BBB (like rapamycin, immunosuppressants, etc.) could work to prevent the onset of the disease as the vagus nerve is not protected by a BBB.

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#637

I don’t know if low CSF levels of melatonin are the cause of PD but there’s an easy way to check if melatonin is neuroprotective:

Sleep disturbances are an early symptom of PD. Especially rapid eye movement (REM) sleep behavior disorder (RBD). People with RBD act out their dreams. The vast majority of people with RBD develop PD or DLB in the 10 years following their RBD diagnosis.

The first line treatment of RBD is melatonin: Clinical trials in REM sleep behavioural disorder: challenges and opportunities 2020

Melatonin, for its more favourable side effect profile, is frequently preferred as initial therapy for RBD. In higher doses (6 to 18 mg at bedtime) melatonin improved frequency and severity of RBD symptoms in up to 70% of patients, as documented in several observational studies. Lower doses (2 mg slow release and 3 mg immediate release) in conjunction with a ‘30 min prior to bedtime, always at the same clock time’ dosing regimen showed improvement in over 90% of patients with iRBD in open-label trials. Unfortunately, a recent placebo-controlled trial using extended-release melatonin was also negative. The mechanism of action of melatonin in RBD is unclear, but the persistent effect after melatonin discontinuation is hypothesised to be due to action on the circadian system. Clinical synucleinopathies are mostly accompanied by a substantial dysfunction of the circadian system. Considering that endogenous melatonin signalling is dampened in synucleinopathies, one can hypothesise that melatonin may improve RBD via a restructuring and resynchronisation of circadian rhythmicity, a hypothesis that needs to be further studied.

The part in bold cites: A two-part, double-blind, placebo-controlled trial of exogenous melatonin in REM sleep behaviour disorder 2010

Patients received placebo and 3 mg of melatonin daily in a cross-over design, administered between 22:00 h and 23:00 h over a period of 4 weeks.
Interestingly, the number of REM sleep epochs without muscle atonia remained lower in patients who took placebo during Part II after having received melatonin in Part I (–16% compared to baseline; P = 0.043). In contrast, patients who took placebo during Part I showed improvements in REM sleep muscle atonia only during Part II (i.e. during melatonin treatment).

Improvements after a discontinuation and a washout period hint at neuroprotection. So, I don’t know why melatonin is only considered symptomatic.

Also: could extended-release be worse than immediate release @John_Hemming? The XR trial failed: Prolonged–release melatonin in patients with idiopathic REM sleep behavior disorder 2020

In this 4-week, randomized, double–blind, placebo–controlled pilot study, 30 participants with polysomnography–confirmed iRBD were assigned to receive PRM 2 mg per day, PRM 6 mg per day, or placebo. Medication was administered orally 30 min before bedtime.
Our findings suggest that PRM may not be effective in treating RBD–related symptoms within the dose range used in this study. Further studies using doses higher than 6 mg per day are warranted.
Although the difference in the RBDQ-KR Factor 2 score decreased from 36.4 to 31.8 at 4 weeks after treatment with PRM 6 mg/day, the standard deviation was relatively high and its p → P value did not show a trend toward statistical significance (P = 0.477).

This XR trial also failed: Melatonin for Rapid Eye Movement Sleep Behavior Disorder in Parkinson’s disease: A Randomised Controlled Trial 2019, “Prolonged-release melatonin 4 mg did not reduce rapid eye movement sleep behavior disorder in PD.”

It should also be easy to look at longitudinal data: are people with RBD who take melatonin less likely to convert to PD than those who do not? Is there a dose–response relationship?

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#638

It’s remarkable how little we actually know about both PD and the mechanism of Rapamycin on the brain.

BBB integrity seems to be an important factor, and Rapamycin might impact this, as might Omega 3 fatty acids.

Here is one article on that issue.
Samuel Barnes and Gary E Fraser - 2021 - Omega-3 fatty acids are associated with blood-brai.pdf (7.7 MB)

Rhonda Patrick has an interesting discussion on needing to potentially move over to Omega 3’s that are in Phospholipid form in inidividuals with ApoE4’s, I suspect the same is likely true for PD.

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#639

We need to understand why DHA supplementation causes depression. And yes DHA needs to be in the brain because high serum DHA is associated with a HIGHER risk of dementia: The shift in the fatty acid composition of the circulating lipidome in Alzheimer’s disease 2024

Higher levels of docosahexaenoic acid in CSF were associated with a lower risk of MCI-to-AD progression.
Higher levels of docosahexaenoic acid in plasma were associated with a greater rate of MCI-to-AD progression.
These observations were also confirmed by Arellanes et al. who demonstrated that only a small percentage of plasma DHA is transported to CSF and that APOE ɛ4 is associated with reduced delivery of this FA to the brain. These findings indicate that DHA concentrations in plasma and CSF are affected by APOE isoforms. A recent investigation has demonstrated that the APOE ɛ4 isoform disrupts BBB function in the hippocampus and medial temporal lobe compared to the other APOE isoforms (ε2/ε3). A large percentage of our progressive MCI patients were APOE ɛ4 carriers (63%), and we found a significant difference in the plasma levels of DHA between carriers and noncarriers of APOE ɛ4 (p = 0.012). Therefore, our results may indirectly indicate a disruption in the transport of DHA from plasma to CSF. In agreement with our hypothesis, Coughlan et al. reported an inverse association between serum DHA levels and spatial navigation performance in APOE ɛ4 carriers. The existence of deficiency in DHA transporters across the BBB is another possibility that may have led to this result. Major facilitator superfamily domain containing 2A (MFSD2A) transports DHA in the form of lysophosphatidylcholine across the BBB. A recent study demonstrated progressively lower blood levels of this transporter in mild and severe AD patients compared to controls. Therefore, it is possible that more rapidly progressing MCI patients have lower levels of transporters, which, in turn, would limit DHA access to the brain (CSF) but increase DHA levels in the blood.

This might align with Rhonda Patrick’s theory.

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Predicting Alzheimers & Dementia (and minimizing risk)
#640

Unfortunately, it looks like Rhonda Patrick is wrong based on this article just published by a Canadian team: Providing lysophosphatidylcholine-bound omega-3 fatty acids increased eicosapentaenoic acid, but not docosahexaenoic acid, in the cortex of mice with the apolipoprotein E3 or E4 allele

And also this French paper: Investigation of Lysophospholipids-DHA transport across an in vitro human model of blood brain barrier 2024

Researchers principally studied the cerebral accretion of Lysophosphatidylcholine (LysoPC-DHA), the furthermost vital Lysophospholipid-DHA (LysoPL-DHA) in blood plasma. Nevertheless, the cerebral bioavailability of other LysoPL-DHA forms including Lysophosphatidylethanolamine (LysoPE-DHA), and Lysophosphatidylserine (LysoPS-DHA) were not extensively examined even though their vital biological functions in the brain.
Furthermore, LysoPS-DHA exhibited the highest intracellular accumulation (10.39 ± 0.49 %) in hBLECs in comparison to all other tested lipids. Finally, differences in 3D structures and molecular electrostatic potential maps calculation of LysoPL-DHA could explain the dissimilar cerebral uptake of LysoPL-DHA. Altogether, our findings raise the novel hypothesis that LysoPS-DHA may represent a preferred physiological carrier of DHA to the brain.

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Predicting Alzheimers & Dementia (and minimizing risk)
#641

A video of Nick Norwitz on ketones for PD. (might reduce progression)
He did RCTs on PD in his PhD so his point of view might be interesting. Ketones are already known to be useful for other brain issues.

#642

The KD is a high-fat, low-carbohydrate diet, which, among other mechanisms [36], may circumvent bioenergetic deficits in PD where affected neurons are unable to efficiently utilize glucose for energy production but likely continue to be able to use ketone bodies such as body beta-hydroxybutyrate, generated in response to a high-fat, low-carbohydrate diet [37]. Ketone bodies may enable neurons to feed electrons into the mitochondrial respiratory chain at complex II, bypassing PD-related deficiencies in complex I metabolism [38]. Four recent RCTs have investigated the feasibility, safety and short-term efficacy of KDs in PD [36]. In an 8-week pilot study comparing a KD to a low-fat diet in 38 participants with PD, both groups showed improvement on all four parts of the UPDRS, with the KD group showing greater improvement in Part I scores [39]. However, worsening tremor and/or rigidity was noted in the KD group 1–4 weeks into the diet intervention, leading to two participant withdrawals. In an open-label, non-controlled pilot study of 16 PD participants on a 12-week KD intervention, significant improvements were seen in UPDRS Part I and total Parkinson Anxiety Scale scores [40]. An 8-week study comparing a ketogenic (n = 7) versus high-carbohydrate (n = 7) diet in individuals with PD and mild cognitive impairment reported improvements in lexical access and memory in the ketogenic diet arm [10]. Another study of 68 participants with PD reported improvements in voice quality following three months of a ketogenic diet [41].

Still, ketones are interesting and trial will soon start about that. That’s also why I think that SGLT2 are great (they increase ketogenesis).

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